25 angioedema of the small intestine masquerading as crohn’s...

C1 inhibitor deficiency andangioedema of the small

intestine masquerading asCrohn’s diseaseKelly W Burak MD FRCPC, Gary R May MD FRCPC

C1 inhibitor (C1-INH) deficiency is a rare disorder thatpresents with angioedema and may be hereditary or ac-

quired. Gastrointestinal involvement may lead to diarrheaand abdominal pain from bowel obstruction. Recurrent at-tacks of bowel angioedema are self limiting, but patients whoare misdiagnosed may undergo unnecessary surgery or de-velop narcotic addiction. Although C1-INH deficiency is arare cause of acute and recurrent abdominal pain, it is impor-tant to recognize this condition. The pathophysiology andmanagement of angioedema are reviewed.

CASE PRESENTATIONA 16-year-old woman presented in May 1998 with severeepigastric abdominal pain, nausea and vomiting. The attackfollowed minor trauma to the abdomen during a fight atschool. There was no hematemesis or melena. She was previ-ously healthy and had no prior gastrointestinal symptoms.She was taking no medications other than an oral contracep-tive that had recently been started. She was a nonsmokerand did not drink alcohol. On examination, she was afebrileand hemodynamically stable. She had mild epigastric ten-

Can J Gastroenterol Vol 14 No 4 April 2000 349

This article was a winning entry in the “Consults in Gastroenterology” Case Study Competition, which was initiated and funded with generoussponsorship of Astra Canada, and it is endorsed by the Canadian Association of Gastroenterology. This generous support indicates AstraCanada’s commitment to very worthwhile educational initiatives in gastroenterology.

Department of Medicine, University of Calgary, Calgary, AlbertaCorrespondence: Dr Kelly Burak, Foothills Hospital, 1403 29th Street Northwest, Calgary, Alberta T2N 2T9. Telephone 403-670-1110, fax

403-270-0995, e-mail [email protected] for publication July 18, 1999

BRIEF COMMUNICATION

KW Burak, GR May. C1 inhibitor deficiency and angioedema ofthe small intestine masquerading as Crohn’s disease. Can J Gas-troenterol 2000;14(4):349-351. A case of C1 inhibitor defi-ciency presenting as localized edema of the small intestine isdescribed. A 16-year-old, previously healthy woman presentedwith recurrent attacks of abdominal pain and vomiting followingminor abdominal trauma. Investigations including computedtomography scan and barium studies confirmed localized edema ofthe jejunum. At laparoscopy, Crohn’s disease was suspected; how-ever, a subsequent enteroscopy was normal. Complement levelsrevealed a low C4 level, and C1 inhibitor deficiency was later con-firmed. Attacks of abdominal pain began after starting oral contra-ceptives and have not returned since stopping the birth controlpill. This rare cause of abdominal pain is examined, and C1 inhibi-tor deficiency and angioedema are reviewed.

Key Words: Angioedema; C1 inhibitor; Oral contraceptives; Small

intestinal obstruction

Déficit en inhibiteur de C1 et angio-oedèmedu petit intestin simulant la maladie de CrohnRÉSUMÉ : Voici un cas de déficit en inhibiteur de C1 qui se manifestesous la forme d’œdème localisé du petit intestin. Une jeune femme de 16ans, auparavant en bonne santé, présente des crises répétitives de douleursabdominales et des vomissements à la suite d’un traumatisme abdominalmineur. Les examens, dont une tomodensitométrie et des explorations aubaryum, confirment la présence d’œdème localisé dans le jéjunum. Lalaparoscopie laisse croire à la maladie de Crohn; toutefois, uneentéroscopie ultérieure s’avère normale. Des examens complémentairesrévèlent une faible concentration de C4, et le déficit en inhibiteur de C1est confirmé plus tard. Les crises de douleurs abdominales ont commencéaprès le début de la prise de contraceptifs oraux et sont disparues depuisl’interruption du médicament. L’article analyse ce cas rare de douleursabdominales et passe en revue le déficit en inhibiteur de C1 etl’angio-oedème.

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derness but no mass or peritoneal signs. Laboratory testsrevealed a hemoglobin level of 115 g/L, and normal electro-lyte, amylase and white blood cell levels. An upper gastroin-testinal series demonstrated thickening of mucosal folds inthe distal duodenum and proximal jejunum, thought to rep-resent an intramural hematoma. There was free fluid in theabdomen and pelvis on abdominal ultrasound. Her pain re-solved over 48 h with intravenous fluids and narcotics.

She returned to the hospital one month later with recur-rent epigastric pain and vomiting. Computed tomography(CT) scan revealed free fluid and prominent thickening ofthe proximal jejunum (Figure 1). An upper gastrointestinalseries confirmed small bowel edema extending from the dis-tal duodenum to 10 cm beyond the ligament of Trietz (Figure2). The initial diagnosis of mural hemorrhage was ques-tioned because a hematoma should have resolved over thepreceding month. Laparoscopy revealed transmural thicken-ing in the first 10 cm of the jejunum. There was thought tobe mild creeping fat in the mesentery. The remainder of thesmall intestine, including the terminal ileum, was normal. Apresumptive diagnosis of Crohn’s disease was made, but hersymptoms had completely resolved in hospital and she wasfollowed without specific therapy. There was no history ofdiarrhea, fever or weight loss. She had no extraintestinalmanifestations of inflammatory bowel disease, and her fam-ily history was unremarkable. Three weeks later, while as-ymptomatic, a repeat upper gastrointestinal series and smallbowel follow-through revealed no abnormalities. Twomonths later, she was readmitted to hospital with another at-tack of colicky epigastric pain. On repeat CT scan, jejunalthickening was once again seen, but there was no peritonealfluid. She was then referred to the authors’ institution for en-teroscopy. The mucosa of the proximal jejunum appearednormal. Jejunal biopsies were normal. The diagnosis of re-current small bowel angioedema was considered. Comple-ment levels revealed a normal C3 and low C4 level at less

than 0.1 g/L (normal 0.13 to 0.45 g/L). The diagnosis of C1-INH deficiency was confirmed with a low C1-INH level atless than 0.05 g/L (normal 0.15 to 0.35 g/L). She had no his-tory of edema of the face, upper airway or extremities. Therewas no history of allergy, urticaria or food intolerance. Shehad no features of autoimmune disease or systemic lupus ery-thematosus. Her family was screened for C1-INH deficiency.One brother had a borderline C4 level at 0.15 g/L, but herparents had normal levels. Because the attacks began after shestarted an oral contraceptive, this medication was discontin-ued. She has subsequently been well and free of attacks.

DISCUSSIONHereditary angioedema (HAE) was first described by SirWilliam Osler in 1888 (1). HAE is an autosomal dominantdisorder with an estimated prevalence of one in 150,000 (2).Defects of the codominantly expressed C1 esterase inhibitorgene located on chromosome 11 are responsible for this dis-order (2). A qualitative deficiency in C1-INH (type I HAE)accounts for 85% of cases. The other 15% of cases have nor-mal C1-INH levels, but the esterase is nonfunctional (type IIHAE) (3). C1 esterase acts as a competitive inhibitor of acti-vated C1r and C1s in the initial steps of the classic comple-ment pathway (Figure 3) (2). It also has inhibitory roles inthe intrinsic coagulation pathway and in the formation ofbradykinin (2).

HAE is diagnosed based on clinical presentation, meas-urement of complement levels and a positive family history.Low levels of C4 are found during and usually between at-tacks as well. If screening C4 levels are low, confirmation ismade by measuring C1-INH levels directly. Patients havenormal C3 levels, and C2 levels are low during attacks butare usually normal between episodes. Patients present withrecurrent bouts of nonpitting edema (angioedema) withoutpruritus or urticaria. HAE affects all races and both sexesequally. It often first appears in childhood and tends to

350 Can J Gastroenterol Vol 14 No 4 April 2000

Burak and May

Figure 1) Computed tomography scan during second admission for ab-dominal pain demonstrating mural thickening in the proximal jejunum(arrow) Figure 2) Upper gastrointestinal series demonstrating mucosal edema in

the proximal 10 cm of the jejunum (arrows)

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worsen during adolescence (4). Almost all patients experi-ence angioedema of the extremities at some time. Two-thirds of patients have orofacial or laryngeal swelling, whichis a life-threatening condition (2). Rarely, patients developpleuritic pain, urinary retention or focal neurological symp-toms from localized brain edema (4). Involvement of the gas-trointestinal tract is common, and patients typically presentwith diarrhea or symptoms of bowel obstruction. Fluid shiftsinto the bowel wall or abdominal cavity may be significantenough to cause hypotension. Acute attacks, often associ-ated with fever and leukocytosis, can mimic an acute abdo-men and result in laparotomy. If recurrent attacks goundiagnosed, patients may develop narcotic addiction andbe labelled drug seekers.

The onset of angioedema is usually gradual over a fewhours and tends to resolve over several days. The most fre-quent trigger of attacks is minor trauma (4). The best exam-ple of this is facial and laryngeal edema precipitated bydental extractions or tonsillectomy. The minor abdominaltrauma that our patient sustained may have been the precipi-tating event for her first episode of angioedema. Women of-ten note an association of HAE attacks with menstruation,and increased frequency of attacks has been noted with theuse of oral contraceptives (5). Our patient had been startedon the birth control pill before the onset of her illness andsince stopping it has been free of attacks.

Acquired angioedema (AAE) has been associated withlymphoproliferative disorders and connective tissue diseasessuch as lupus (3). These cases can be distinguished from he-reditary forms in that they usually present in older patientswithout a family history. Although these patients have nor-mal C1-INH production, abnormal proteins in the serumtrigger increased catabolism of C1-INH (type I AAE). Rarecases of autoantibody production against C1-INH have beendescribed (type II AAE) (6). Angiotensin-converting en-zyme (ACE) inhibitors are a well-recognized cause ofangioedema. There are several case reports of ACE inhibi-tors causing isolated small bowel angioedema (7,8). Bradyki-nin, a mediator of angioedema, is degraded by ACE;therefore, no patient with HAE should receive ACE inhibi-tors for fear of precipitating attacks of angioedema.

The management of acute attacks of angioedema focuseson supportive care with intravenous fluids for hypotensionand narcotics for pain control (2,4,9). Maintenance of theairway is of utmost importance. There is no evidence to sup-port the use of adrenaline, histamine antagonists or corticos-teroids during acute attacks (2). Purified C1-INH concen-trate is available and can shorten the duration of an acuteattack (10). Fresh, frozen plasma may be useful but carries arisk of transfusion reactions and infection transmission, andpossibly fuels the complement cascade (9). Patients whohave had airway edema or frequent abdominal attacks arecandidates for maintenance therapy in the form of attenu-ated androgens using danazol or stanozolol. They increaseC1-INH levels but are associated with masculinizing side ef-fects and should not be used in prepubertal patients. Alter-natively, antifibrinolytic agents such as epsilon-amino-

caproic acid can prevent angioedema by inhibiting plasminactivity, although they have no effect on C1-INH levels.C1-INH infusions on a weekly basis can be used for mainte-nance therapy. Patients with HAE who require dental ex-tractions or surgery should receive prophylaxis with andro-gens two weeks in advance or infusions of C1-INH or freshfrozen plasma the day of surgery. Treatment of the underly-ing neoplasm is most important in AAE type I, and immuno-suppression or plasmapheresis can be used for AAE type II.Currently, our patient is being managed conservatively, al-though purified C1-INH has been made available to the pa-tient’s local hospital for use in future attacks.

SUMMARYC1-INH is a rare disorder that often presents with abdominalcomplaints that can mimic other conditions. It is importantto recognize small intestinal angioedema because it has a dis-tinct pathogenesis and requires unique treatment.

REFERENCES1. Osler W. Hereditary angioneurotic edema. Am J Med Sci

1888;93:362-7.2. Huston DP, Bressler RB. Urticaria and angioedema. Med Clin North

Am 1992;76:805-40.3. Kulp-Shorten CL, Callen JP. Urticaria, angioedema and

rheumatologic disease. Rheum Dis Clin North Am 1996;22:95-115.4. Whaley K, Sim B, He S. Autoimmune C1-inhibitor deficiency.

Clin Exp Immunol 1996;106:423-6.5. Jacobs RL, Hoberman LJ, Goldstein HM. Angioedema of the small

bowel caused by an angiotensin-converting enzyme inhibitor.Am J Gastroenterol 1994;89:127-8.

6. Abdelmalek MF, Douglas DD. Lisinopril-induced isolated visceralangioedema: review of ACE-inhibitor-induced small bowelangioedema. Dig Dis Sci 1997;42:847-50.

7. Orfan NA, Kolski GB. Angioedema and C1 inhibitor deficiency.Ann Allergy 1992;69:167-72.

8. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema:the clinical syndrome and its management. Ann Intern Med1976;84:580-93.

9. Moore GP, Hurley WT, Pace SA. Hereditary angioedema. Ann EmergMed 1988;17:1082-6.

10. Gadek JE, Hosea SW, Gelfand JA, et al. Replacement therapy inhereditary angioedema. N Engl J Med 1980;302:542-6.

Can J Gastroenterol Vol 14 No 4 April 2000 351

C1 inhibitor deficiency and intestinal angioedema

Figure 3) Pathophysiology of angioedema. C1 inhibitor (C1-INH) actsin the classical complement cascade and also the intrinsic coagulationpathway and kinin-forming system. Bradykinin and the kinin-like activ-ity of C2b are important mediators of angioedema

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